Sites of action of phencyclidine. I. Effects on the electrical excitability and chemosensitive properties of the neuromuscular junction of skeletal muscle

The effects of phencyclidine (PCP) were studied on the electrical and chemosensitive properties of the neuromuscular junction of skeletal muscles as well as on the binding of properties of the neuromuscular junction of skeletal muscles as well as on the binding of ligands to acetylcholine (ACh) receptors in the electric organ membranes of the electric ray. PCP potentiated both the directly and the indirectly elicited muscle twitch, an effect which occurred with a simultaneous prolongation of the falling phase of the action potential blockade of delayed rectification and only a slight decrease in the rate of rise of spike activity. The prolongation of the action potential was also increased as a function of the frequency of nerve stimulation. In contrast to the marked potentiation of directly elicited muscle twitch, indirect muscle twitch was only transiently potentiated at concentrations lower than 60 μM and subsequently blocked. Indeed, at concentrations higher than 60 μM, blockade of neuromuscular transmission occurred with little or no potentiation of the indirectly elicited twitch. Resting membrane potential and passive electrical properties were little affected by PCP. At high concentrations of PCP the miniature endplate potentials were blocked, as were the ACh sensitivities of the junctional region of innervated muscles as well as the extrajunctional region of chronically denervated muscles. PCP did not prevent the irreversible effects of α-bungarotoxin on ACh sensitivity in junctional regions of the innervated and extrajunctional regions of chronically denervated muscles. At these effective concentrations (i.e., 1 to 100μM) PCP caused negligible inhibition of ACh-esterase. In addition, since PCP did not inhibit the binding of [ ³H]ACh or [ ¹²⁵I]α-bungarotoxin to the ACh receptors, it was suggested that the inhibition of ACh-receptor-regulated ionic conductances was not due to the inhibition of ACh-receptor binding sites. Inhibition was possibly due to an interaction with the ionic channel of the ACh receptor. Furthermore, the effect of PCP on the electrical excitability of muscle membrane, shown by the marked prolongation of the action potential and inhibition of delayed rectification, suggested that the agent caused significant blockade of potassium conductance. This effect most likely could account for the potentiation of the muscle twitch.